tbuckley/cabot-search huggingface dataset:
CNSC-20. PROTEOMIC ANALYSIS OF GLIOMA BIOPSIES SHOWS CONSISTENCY WITH GLIOMA GRADING
Authors: Severina Leu, Jean-Louis Boulay, Michè le Amer, Marie-Françoise Ritz, Florian Samuel Halbeisen, Alexander Schmidt, Katarzyna Buczak, Gregor Hutter
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioma are currently classified according to integrated histopathologic and molecular genetic (WHO 2021 classification) as well as methylomic criteria (Capper 2018). However, little is known about proteomic profiling of these subgroups , which may reveal specific biomarkers and pathways potentially activated or inactivated. Material and METHODS Eighty-six glioma biopsy samples were prospectively collected from patients undergoing surgery at the University Hospital of Basel between 2017 and 2019. Samples were classified into seven distinct glioma subgroups based on integrated WHO 2016 and methylome profiling criteria. Proteins were extracted from fresh frozen samples devoid of necrosis/haemorrhage and processed for mass spectrometry analysis. RESULTS For each tumour sample, a total of 8’855 proteins were identified and quantified. 950 proteins were differentially expressed between at least two glioma subgroups. Strikingly, most significant differences in expression are related to tumor grading rather than to glioma subgroups. Proteins SSDH and GABT, involved in Gamma-aminobutyric acid (GABA) catabolism, show the strongest increase between low grade glioma (LGG) and high grade glioma (HGG), whereas S10AA and ANXA2, part of pathways involved in coagulation, cell adhesion and immune response, appear increased in HGG. CONCLUSION Tumor grading turns out to be dominant over genetic and epigenetic criteria for proteomic classification. Most significant protein level variations may represent potential glioma grade-specific therapeutic targets.
DDDR-22. TRANSLATION OF THE PDGFRA/KIT INHIBITOR AVAPRITINIB FOR PEDIATRIC HIGH-GRADE GLIOMA
Authors: Lisa Mayr, Maria Trissal, Kallen Schwark, Jenna Labelle, Seongbae Kong, Andrew Groves, Jeffrey Supko, Olivia Hack, Joana Marques, Eshini Panditharatna, Frank Dubois, Noah Greenwald, Pratiti Bandopadhayay, Keith Ligon, Julia Furtner-Srajer, Liesa Weiler-Wichtl, Ulrike Leiss, Verena Rosenmayr, Sibylle Madlener, Natalia Stepien, Daniela Lötsch-Gojo, Christian Dorfer, Karin Dieckmann, Amedeo Azizi, Armin Guntner, Hana Palova, Ondrej Slaby, Petra Pokorná, Rameen Beroukhim, Christof Kramm, David T Jones, Jaroslav Štěrba, Leonhard Mullauer, Christine Haberler, Nisha Perez, Sean Kim, Anthony Hsieh, Sasa Dimitrijevic, Mary Skrypek, Nina Martinez, Daniel Bowers, Mariella Filbin, Johannes Gojo, Carl Koschmann
Journal: Neuro-Oncology (2022)

Abstract Pediatric high-grade glioma (pHGG) is an incurable disease with a median survival of less than 6 months post-progression and no effective targeted therapy. PDGFRA is commonly altered in pHGG, but targeting PDGFRA in this disease has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib is a novel and CNS-penetrant PDGFRA/KIT inhibitor that is FDA-approved for adults with unresectable or metastatic PDGFRA exon 18-mutant gastrointestinal stromal tumor (GIST) and is being studied in CNS tumors. We performed a pre-clinical and clinical assessment to determine the potential suitability of avapritinib therapy in PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed PDGFRA amplification and mutation in 10.2% and 6.1% of pHGG, respectively. Additionally, PDGFRA expression in the absence of genetic events was significantly increased in H3K27-altered diffuse midline glioma (DMG) compared to H3-wildtype pHGG. Avapritinib performed well in: (i) mutant PDGFRA enzyme inhibition and wildtype inhibition at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), and (iv) proliferation/pPDGFRA reduction in PDGFRA-amplified and mutant pHGG cell lines. Avapritinib treatment in an aggressive PDX model of pHGG resulted in significant survival benefit. We pursued treatment of eight pediatric and young adult HGG patients with avapritinib across seven institutions. Patients were a mixture of local (N = 4) and metastatic disease (N = 4); all patients were post-initial radiation, with 7/8 having progressed on prior treatment. 7/8 patients had PDGFRA amplifications or mutations, and 7/8 had H3K27M mutations. Therapy was generally well-tolerated. 4/8 patients showed radiographic response to avapritinib, with one patient demonstrating complete response of target lesion and remains on therapy. Avapritinib levels in patients’ CSF and brain tumor tissue reached micromolar levels. These results demonstrate that avapritinib is a potent, selective, and CNS-penetrant PDGFRA/KIT inhibitor that is promising for further study in pHGG with relevant alterations.
EPCO-05. DIFFERENTIAL MOLECULAR PROFILING OF IDH WILD TYPE GLIOBLASTOMA SURVIVORS REVEALS THE ASSOCIATION OF NEOANTIGEN QUALITY WITH EXCEPTIONAL LONG SURVIVAL
Authors: Fulvio D'Angelo, Luciano Garofano, Kosuke Aoki, Michele Ceccarelli, Anna Lasorella, Marc Sanson, Antonio Iavarone
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor. Despite intensive multimodal treatment, the prognosis of GBM patients is poor with the median overall survival under 15 months. Defining the genetic profiles of rare long-term GBM survivors may provide insights into the molecular basis of GBM progression. IDH mutations have been identified as a favorable prognostic factors, and define a clinically and molecularly distinct group of GBM. Additional molecular mechanisms underlying the prolonged survival in IDHwt GBM patients remained unclear. Therefore, we explored the molecular profiles of 71 IDHwt GBM homogeneously treated patients exhibiting disproportionate survival. The cohort included 36 short-term survivors that deceased within 1 year after diagnosis (median survival of 7 months) and 35 long-term survivors exhibiting an exceptional survival above 4 years (median survival of 88 months). The differential genetic landscape of short- and long-term IDHwt GBM survivors outlined similar mutation load and few differences in the frequency of recurrent alterations, including chromosomes 19 and 20 duplication significantly overrepresented in long-term survivors. To assess the potential impact of T lymphocyte neoantigen-mediated activation towards extended GBM survival, we inferred the restricted HLA binding affinity of the somatic mutations and applied the immune fitness model to accurately predict high-quality neoantigens. Although the general neoantigen burden remained unvaried between short- and long-term survivors, we found that the immune quality of the predicted neoantigens is significantly higher in the patients with exceptional long survival. Moreover, the immune deconvolution of the tumor microenvironment from the gene expression data indicated the presence of CD8+ T lymphocytes and pro-inflammatory macrophages in samples harboring high-quality neoantigens from long-term survivors. This study identified the neoantigen quality as a main distinctive feature of exceptionally long-term survivors supporting the key role of cellular-mediated immune response to restrict tumor progression in IDHwt GBM.
DDDR-31. THE THERAPEUTIC POTENTIAL OF THE LONG NON-CODING RNA LNC-HLX-2-7 IN GROUP 3 MEDULLOBLASTOMAS IN CHILDREN
Authors: Keisuke Katsushima, Menglang Yuan, Bongyong Lee, Stacie Stapleton, George Jallo, Sudipta Seal, Charles Eberhart, Ranjan Perera
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the non-coding RNA genome, in particular long non-coding RNAs (lncRNAs), contributes to MB formation and tumor progression. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 MBs. In this study, we report that lnc-HLX-2-7 RNA specifically accumulates in the HLX (host gene of lnc-HLX-2-7) promoter region and activates HLX expression by recruiting multiple factors including enhancer elements. RNA sequencing and chromatin immunoprecipitation revealed that HLX directly binds to the promoters of several tumor-promoting genes, including MYC, and activates their expression. Furthermore, intravenous treatment with antisense oligonucleotides targeting lnc-HLX-2-7 coated with cerium-oxide nanoparticle (CNP-lnc-HLX-2-7) reduced tumor growth (40-50%) in intracranial MB xenograft mouse model (n = 10, p &amp;lt; 0.01, t-test). We found that the combinatorial therapy of CNP-lnc-HLX-2-7 and cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared to CNP-lnc-HLX-2-7 monotherapy (n = 10, p &amp;lt; 0.01, t-test) only. We report here the importance of the lnc-HLX-2-7-HLX-MYC axis in regulating group 3 MB progression and provide a strong rationale for using lnc-HLX-2-7 as a specific and potent therapeutic target for the group 3 MBs in children.
IMMU-32. SPERMIDINE DRIVES GLIOBLASTOMA PROGRESSION VIA SELECTIVE MODULATION OF THE IMMUNE SYSTEM
Authors: Kristen Kay, Defne Bayik, Zeneng Wang, J Mark Brown, Stanley Hazen, Justin Lathia
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is incurable despite aggressive standard of care treatments (maximal safe surgical resection, radiation, chemotherapy). GBM therapeutic resistance is due to multiple factors, including tumor heterogeneity and a highly immunosuppressive environment. Naturally occurring polyamines have been identified as a putative therapeutic target in other cancers based on their increased presence and function in normal conditions; they are critical for cell growth and proliferation and cellular functions including autophagy and apoptosis. While polyamines are increased in GBM patients, little is known about their impact on GBM growth. In syngeneic immune competent mouse glioma models (GL261, SB28), mass spectrometry data revealed that spermidine (SPD) – a member of the polyamine family – is increased in tumor tissue as compared to non-neoplastic control brain tissue (sham implanted animals). To test the impact of SPD on tumor growth, we treated mouse glioma models with exogenous SPD and found treatment significantly decreased survival. However, in immunocompromised host mice, no such difference was observed, indicating the mechanism through which SPD is driving GBM progression likely involves immune system alterations. Depletion of myeloid derived suppressor cells in vivo via anti-Gr-1 antibody rescues the decrease in survival caused by exogenous SPD, indicating that SPD drives GBM by affecting immune-suppressive cell subsets, namely MDSCs. To assess if SPD is associated with more aggressive GBM growth in human patients, we are currently analyzing polyamine levels in human GBM samples of long vs short term survivors. We are also exploring the effect of dietary polyamines on GBM via the gut-brain-microbiome axis, as polyamines are enriched in many foods and produced by a subset of commensal gut microbes. Understanding the interactions between polyamines, the tumor microenvironment, and the immune response provide a new mechanism for GBM regulation and identify opportunities to alter the environment in the body to enhance immunotherapeutic efficacy.
EPCO-23. DYSFUNCTION OF LARGE H3K9ME3 DOMAINS IN ATRX DEFICIENT GLIOMAS INDUCES GENETIC REARRANGEMENTS AND LATENT DEVELOPMENTAL SIGNALING NETWORKS THROUGH SUPER-ENHANCER LANDSCAPES
Authors: Prit Benny Malgulwar, Carla Danussi, Anand Singh, Ajay Kumar Saw, Kunal Rai, Jason Huse
Journal: Neuro-Oncology (2022)

Abstract Somatic alterations in ATRX (Alpha Thalassemia/Mental Retardation Syndrome X-linked), a member of SWI/SNF family chromatin regulator has been found to be frequently mutated in diffuse gliomas and defines molecular subtypes with aggressive behavior. Mechanistically, ATRX regulates incorporation of histone H3.3 into chromatin sites across the genome, maintains alternative lengthening of telomeres and establishes genomic distribution of polycomb responsive genes. To understand in depth role of ATRX in gliomas, we performed ChIP-seq and/or Cut-and-tag for histone marks that define active transcription, enhancers, repressors, gene bodies and CTCF on Atrx intact and deficient mNPCs (mouse Neural Progenitor Cells). Our integrated analysis reports depletion of H3K9me3 loci’s that coincidently enriched with Atrx binding sites and Lamina-Associated Domains with genes enriched for cell cycle, motility and chromosome organization. This chromatin perturbations at heterochromatin domains was further confirmed in our Hi-C analysis with switching of A-B and B-A compartments, reorganization of TADs with occasional CTCF marks and gain of novel interacting loops that showed gene expression leakage required for gliomagenesis using Capture Hi-C. Notably, we observed aberrant levels of endogenous retroviral elements (ERVs) family members, including upregulation of Line-1 elements in mNPCs and patient derived glioma stem cells (GSCs) and our analysis shows increased copy number variations in ATRX deficient gliomas as a consequence of Line-1 activation in these subsets of tumors. Finally, our integrated omics- analysis demonstrates enrichment of super-enhancers in Atrx deficient background with several putative druggable candidates for clinical benefits. As an example, we show presence of H3K27ac super-enhancer over HOXA locus and targeting pan-HOXA genes using small inhibitor peptides diminished proliferation and migration of mNPCs and GSCs with increased in cell apoptosis with alterations in downstream developmental signaling pathways. To summarize,our data establishes tangible links between Atrx deficiency and multiscale dysregulated cellular phenotype in gliomas with identifying novel targets for therapy.
BIOM-39. P-ERK ASSOCIATION WITH OVERALL SURVIVAL IN RECURRENT GBM PATIENTS TREATED WITH INTRACEREBRAL ADMINISTRATION OF PD-1 AND CTLA-4 BLOCKING ANTIBODIES
Authors: Victor Arrieta, Johnny Duerinck, Kirsten B Burdett, Wietse Geens, Julia Katharina Schwarze, Andrew Gould, Li Chen, Matthew McCord, Craig Horbinski, Hui Zhang, Roger Stupp, Bart Neyns, Adam M Sonabend
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Anti-PD-1 immunotherapy induces clinical responses in a subset of glioblastoma (GBM) patients. We previously reported that ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples is predictive of overall survival (OS) following adjuvant anti-PD-1 therapy in two independent cohorts of recurrent GBM patients. METHODS Following the Remark criteria for biomarker validation, we investigated p-ERK as a predictive of OS in 24 evaluable tumor samples of recurrent GBM patients from a clinical trial. These patients underwent intracerebral administration of immune checkpoint inhibitors as part of a phase I clinical trial where intracerebral administration of ipilimumab (10 mg) or ipilimumab (5 mg) and nivolumab (10 mg) followed by postsurgical intravenous nivolumab (10 mg) was evaluated (NCT03233152; Duerinck J, et al. JITC, 2021). We quantified cell density of p-ERK+ cells in tumor regions. For exploratory purposes, patients were divided in 3 groups (n=8 per group) bases on p-ERK cell density. RESULTS We observed an incremental OS with high p-ERK GBM patients exhibiting a median OS of 81.6 weeks (95% CI 33.86-NA), intermediate p-ERK median OS of 43.1 weeks (95% CI 33.14-NA), and low p-ERK group with a median OS of 19.3 weeks (95% CI 16.14-NA). A Cox proportional hazards model adjusted for age and IDH mutant status showed a trend for p-ERK association with favorable OS (HR= 0.77, 95% CI 0.6-=1.01, P=0.056). CONCLUSIONS While the number of patients analyzed is relatively small, this study suggests the potential predictive power of p-ERK in an independent prospective GBM cohort treated with an alternative and unique administration approach of immune checkpoint blockade.
DDDR-20. TARGETING THE SELECTIVE VULNERABILITY OF IDH-MUTANT GLIOMA WITH ZOTIRACICLIB
Authors: Ying Pang, Guangyang Yu, Alice Ranjan, Herui Wang, Zach Sergi, Olga Kim, Mythili Merchant, Meili Zhang, Hua Song, Wei Zhang, Dionne Davis, Mark Gilbert, Zhenggang Liu, Jing Wu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND IDH mutations are common in diffuse gliomas and confer an increased dependency on oxidative mitochondrial function. Zotiraciclib, a multi-kinase inhibitor, not only suppresses CDK9-mediated gene transcription process but also causes mitochondrial dysfunction in preclinical models. We investigated the selective activity of zotiraciclib in IDH-mutant gliomas. METHODS Cytotoxicity of zotiraciclib was determined in patient-derived glioma cells with/without IDH mutations. Immunoblotting and flow cytometry were used to evaluate the cell death pathways. Real-time ATP production was measured by Seahorse assay. RESULTS The EC50 of zotiraciclib in IDH-wt cells was twice as high as in IDH-mutant cells. In low-dose zotiraciclib (15nM)-treated IDH-mutant cells, RNA Pol II phosphorylation and expression of antiapoptotic proteins, including XIAP, MCL-1 and survivin were decreased significantly. Cleaved caspase 3/7, 8, 9 and LC3B were also detected in treated IDH-mutant cells but not in IDH-wt cells, suggesting activation of intrinsic and extrinsic cell apoptosis pathways, and subsequent autophagy of IDH-mutant cells. Low-dose treated IDH-mutant, but not IDH-wt cells, induced decreased expression of a panel of mitochondrial respiration genes, and mitochondrial respiration complexes, cellular ATP depletion and increased ROS production, suggesting a greater disruption of mitochondrial function in zotiraciclib-treated IDH-mutant cells. Zotiraciclib treatment prolonged the survival in mice bearing intracranial IDH-mutant gliomas (30 days in DMSO-treated group vs 33 days in zotiraciclib-treated group, p = 0.01), but not in mice with glioma established with the isogenic IDH-wt glioma cells (18 days in DMSO-treated vs 20 days in zotiraciclib-treated group, p = 0.10). CONCLUSIONS There is selective activity of zotiraciclib in IDH-mutated glioma. Low-dose exposure of zotiraciclib induces cell death and suppresses transcriptional process and mitochondrial biogenesis in IDH-mutant glioma, not in IDH-wt tumors. These findings support a clinical trial testing zotiraciclib in IDH-mutated glioma. The treatment efficacy seen even at low concentrations further supports testing it as a single agent, thereby reducing toxicity concerns.
EPCO-16. ESTIMATING THE DIFFERENTIATION POTENTIAL AND PLASTICITY OF GLIOBLASTOMA CELLS USING STATISTICAL MECHANICS
Authors: Adam Lång, Ida Larsson, Rebecka Jörnsten, Sven Nelander
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common form of adult brain tumors and patients diagnosed with GBM face a very dismal prognosis with a median survival rate of 15 months. The challenges in treating GBM are many, there is a complex cellular and molecular heterogeneity, both between patients and within individual tumors. In a single tumor, individual cancer cells adopt a variety of stem-like, progenitor-like, and more differentiated phenotypes (a.k.a. cell states). Recent advances in single-cell technology have made it possible to detect this diversity of cellular states, but yet we lack a good explanation for how the states arise and if transitions between states can be exploited to therapeutic ends. We here propose a new computational strategy to measure the differentiation potential of GBM cells, based on the Ising models from statistical mechanics. Originally used to model coupled magnets on a lattice, the Ising models can be generalized to represent the probability of a particular configuration of any system of n variables. We show that the models can be fitted to high-dimensional single cell data in a matter of seconds by solving a convex optimization problem, and that the models help explain cell differentiation in terms of minimization of an energy function of the system. In our on-going work we have fitted the model to single cell data from our previous work on state transitions in GBM (Larsson, Dalmo et al, Molecular Systems Biology 2021) and shown that the predicted differentiation potential of cell states is consistent with the cell state hierarchies derived from lineage tracing experiments. Moving forward, we are now exploring how the Ising models can be used to model state transitions in GBM and to predict the effect of targeted therapy on the cell’s differentiation potential.
NCOG-18. OVERALL SURVIVAL VARIATION DUE TO THE TIMING OF POST-SURGICAL RADIATION IN HIGH-GRADE GLIOMAS
Authors: Allison Lowman, Samuel Bobholz, Savannah Duenweg, Fitzgerald Kyereme, Elizabeth Cochran, Dylan Coss, Jennifer Connelly, Wade Mueller, Mohit Agarwal, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Grade III and IV astrocytomas and glioblastomas are recognized as high-grade gliomas with aggressive heterogenous natures that carry with them a low overall survival (OS). Standard treatment currently involves surgical resection followed by radiation (RT) and concomitant chemotherapy. Despite this standard pathway, there is often disagreement in the optimal timing of radiation initiation post-surgery. In this study, we examined a subset of patients diagnosed with primary high-grade gliomas that underwent radiation following surgery at varying time frames. METHODS 53 patients from our brain cancer bank with surgical diagnosis of high-grade gliomas were retrospectively analyses for this study. All patients were grouped into three cohorts based on the timing of the initiation of radiation post-surgery. Group 1 RT &amp;lt; 4 weeks, Group 2 RT 4-5 weeks, and Group 3 RT &amp;gt; 5 weeks post-surgery. Overall survival was calculated in days from initial surgical resection to time of death. RESULTS Across the three patient cohorts, Group 1 included 9 patients (mean OS 430 days), Group 2 had 18 patients (mean OS 597 days), and Group 3 had 26 patients (mean OS 895 days). Overall survival trended towards a difference between the three radiation timing groups, with Group 3 showing better survival outcomes compared to Group 1 (p=0.07). CONCLUSIONS This current study demonstrates a positive outcome with increased time between surgical intervention and initiation of radiation and concomitant chemotherapy. While we did not correct for additional treatment outside of standard clinical care, we would expect to observe similar trends. Despite these promising results for treatment planning, future research in larger cohorts is necessary to investigate possible molecular markers that may also impact treatment response and overall survival.